The present invention relates to a method and device to detect and identify pathologies inside orifices of a living subject and more specifically to a method and device to detect and identify cancer. Particular embodiments are configured for detection of colon cancer, cervical cancer, lung cancer, cancer of the esophagus, and stomach cancer. More specifically the present invention relates to a method and device including passive detection and identification of different kinds of internal tumors, lesions and cancers by combined analyses of visible and infrared optical signals based on integral and spectral regimes for detection and imaging leading to early warning and treatment of potentially dangerous conditions.
A few common cancers associated with orifices and the current art methods of diagnosis follow:
Gastric cancer is the seventh most frequent cause of cancer mortality in the US. The main screening methods for gastric cancer are:
Upper endoscopy imaging—A small visible spectrum camera and light source are attached to a flexible guide and inserted through the throat and into the stomach of a patient. A doctor examines the resulting images to detect abnormalities. Some improvements such as zoom capable cameras are in development. Nevertheless, all current visible imaging techniques have a few significant limitations. Firstly, detection of abnormalities is subjective and dependent on the expertise and the alertness of the examining doctor. Furthermore, while observed images are useful for detecting abnormal lesions, positive identification requires a biopsy to determine the lesions' status.
Endoscopic confocal microscopy—A conventional visible light endoscope is fitted with a probe capable of producing microscopic images. A pathologist uses the microscopic images to identify cancer in-vivo (without requiring examination of tissue in a biopsy). The technique is still in the stage of development and is currently exceedingly expensive. Furthermore, the method is based solely on visible inspection by a doctor and therefore the detection and identification are subjective and dependent on the alertness and subjective judgment of the examining doctor. Also, since the field of few the microscopic image is about 300 μm, there is a danger (depending on the expertise of the operator) that the microscopic imaging will miss an important feature of the abnormality.
Barium upper gastrointestinal radiography—A patient drinks a barium-containing solution that coats the lining of the esophagus, stomach and first portion of the small intestine. Then the resulting distribution of the barium is measured using x-rays. In and of itself, this test is not accurate, but it is useful in helping to identify lesions detected using other tests.
Endoscopic ultrasound—A transducer probe placed into the stomach through the mouth or nose uses sound waves to produce images of internal organs. The transducer emits sound waves and detects the echoes bounced off internal organs. Endoscopic ultrasound is useful for staging depth of tumor invasion. Nevertheless, endoscopic ultrasound cannot be used to for early detection or identification of tumors because ultrasound cannot detect young tumors smaller than the wavelength of sound (of order 1 cm) and because many different objects produce similar ultrasound echoes.
Computed tomography (CT)—The subject is scanned with x-rays over successive cross-sections. The procedure produces good sensitivity and accuracy, but has the major drawback of exposing the subject to significant quantities of potentially dangerous x-radiation.
Positron emission tomography (PET)—Radioactive glucose is injected into the subject's vein. Because cancers use sugar much faster than normal tissues, locations of high concentrations of the radioactive glucose are associated with cancer. Thus, by scanning the subject one can spot cancer that has spread beyond the stomach. PET is a useful test for staging the cancer. Nevertheless, PET scans are currently unable to detect or identify stomach cancer in its early stages.
Magnetic resonance imaging (MRI)—The subject is scanned using radio waves after exposure to strong magnets. A computer translates the pattern of radio waves given off by the tissues into a very detailed image of parts of the body. The procedure is extremely expensive and at present MRI appears to perform well in evaluating the local and distant extents of cancer but less well at detecting unsuspected primary tumors.
Endoscopic auto fluorescence spectroscopy—A new technique based on active excitation of tissue by applying UV light via an endoscope. Endogenous visible fluorescence spectra emitted by the tissue is collected with a fiber optic probe and analyzed with a spectrograph. While auto fluorescence spectroscopy has shown promise when applied to detection of skin cancer, auto fluorescence spectroscopy has disadvantages in internal studies. Firstly auto fluorescence spectroscopy requires subjecting potentially sensitive internal tissues to ultraviolet light stimulation. Secondly, auto fluorescence signals are masked by reflected visible light. Thus current art reflected light measurements cannot be made simultaneously to auto fluorescence measurements. This means that auto fluorescence cannot be used in addition to current reflected light techniques for improved detection of abnormalities. Attempts to apply auto fluorescence for diagnosis of internal abnormalities [see Mayinger, B., M. Jordan, T. Horbach, et al., “Evaluation of in vivo endoscopic auto fluorescence spectroscopy in gastric cancer”, Gastrointestinal Endoscopy, vol. 59, No. 2, 2004, pp. 191-198] have not provided satisfactory results.
Colorectal cancer is the third most common malignant neoplasm worldwide; the following methods are used for colorectal screening:
Fecal Occult Blood test—The presence of hidden blood is detected in the stool. Blood in the stool that is not visible is often the first warning sign that a person has a colorectal disorder. The disadvantages of this method are that it detects blood in stool, but not its cause and False-positive and false negative results are common. Thus a more sensitive and precise test is needed.
Flexible sigmoidoscopy and colonoscopy—These techniques are similar to upper endoscopy except that the endoscope is called a sigmoidoscope or colonoscope and is inserted in the rectum rather than the throat. These techniques can discover 50% to 65% of polyps and are subject to all of the limitations of upper endoscopy.
Virtual Colonoscopy (CT Colonoscopy)—Refers to examination of computer-generated images of the colon from data obtained by CT or MRI machines. The performance of this non-invasive method depends heavily on the size of the lesion; it can miss polyps smaller than 10 mm and generally suffers from the limitations of CT and MRI imaging mentioned above.
DNA Mutation in the Stool—This new non-invasive method is based on the detection of mutations in faucal DNA. At present the cost of this technique is high and sensitivity results are the same as colonoscopy.
Barium Enema—Flow of barium is monitored on an x-ray fluorescence screen. This method has a low rate of detection even of large adenomas, but the technique is valuable in cases in which the colonoscopy does not reach the lesion.
Cervical cancer is cancer of the uterine cervix, the portion of the uterus attached to the top of the vagina. Ninety percent of cervical cancers arise from the flattened or “squamous” cells covering the cervix. Most of the remaining 10% arise from the glandular, mucus-secreting cells of the cervical canal leading into the uterus. This cancer is the 2nd most common cancer in women worldwide. The following methods are used for cervical screening/detection:
Pap smear—This screening examination is obtained by collecting a sample of cells from the cervix with a wooden or plastic spatula and brush. Specimens are placed on glass slides and examined by a special pathologist/cytologist. If abnormalities are found, women are typically asked to return for colposcopy. The quality of the Pap smear can be compromised by inflammatory exudate, or failure to sample the transformation zone. As a result, a relatively high false-negative rate of 20% pap smears might cause failure to diagnose pre-invasive disease.
Colposcopy—Colposcopy uses a magnifying lens to view the surface of the cervix under white and green light after a mild vinegar solution is applied. If pathologic areas are seen, a biopsy is taken. This method is not performed in real time and has the disadvantages of other forms of visible light endoscopy as described above. Particular, visible light endoscopy is subjective and depends on physician experience and alertness.
None of the above techniques of detection are capable of positively identifying tumors. Therefore according to current art distinguishing tumors from other benign or pathological conditions requires biopsy. Biopsies have many obvious disadvantages: firstly a biopsy requires intrusive removal of tissue that can be painful and expensive. Particularly in internal cavities and more particularly in the stomach and intestines, biopsies run a high risk of serious complications. These complications can lead to very painful conditions (including ulcers), they can force limiting diet or activity of a patient for significant periods of time and complications may even require treatment and drastic intervention (for instance surgery). Only a very limited number of sites can be biopsied in one session. Furthermore, biopsy samples must be stored and transported to a laboratory for expert analysis. Storage and transportation increase the cost, increase the possibility that samples will be mishandled, destroyed or lost, and also cause a significant time delay in receiving results. This time delay means that examination follow up requires bringing the patient back to the doctor for a separate session. This increases the inconvenience to the patient, the cost and the risk that contact will be lost or the disease will precede to a point of being untreatable. Furthermore, the waiting period causes significant anxiety to the patient. Finally, interpretation of biopsies is usually by microscopic analysis, which results in qualitative subjective results that are not well suited to consistent interpretation.
Therefore, in medical diagnosis, there is great interest improved sensitivity, safe non-operative detection technologies capable of revealing internal cancers in their early stages and also in improved techniques for identification to differentiate between cancer, benign conditions and other pathologies of internal tissue.
Optical methods for have long been applied to early detection and identification of skin cancer [Gniadecka, M., H. C. Wulf, N. Nymark Mortensen, O. Faurskov Nielsen and D. H. Christensen “Diagnosis of Basal Cell Carcinoma by Raman Spectroscopy”, JOURNAL OF RAMAN SPECTROSCOPY, 28, 125-129, 1997; Brooks, A., N. I. Afanasyeva, V. Makchine, R. F. Bruch, S. F. Kolyakov, S. Artjushenko and L. N. Butvina, “New Method for Investigations of Normal Human Skin Surfaces in vivo Using Fiber-optic Evanescent Wave Fourier Transform Infrared Spectroscopy (FEW-FTIR)”, Surf. Interface Anal., 27, 221-229, 1999]. Visible light examination, spectral analysis, digital imaging using active regimes, and thermal imaging methods have been applied.
In the spectral regime electromagnetic radiation signal intensities are measured in various frequency bands generally based on perceiving reflected light in the visible to NIR bands. Identification of specific abnormalities is based on information about the corresponding “signature” of radiation associated with the corresponding anomaly measured in the frequency domain.
In skin cancer studies, the method of thermal imaging has been used to produce color images of skin tumors or skin pathological abnormalities. This passive integral regime detects differences in patterns of MIR emissions from normal and pathological tissues. The results of this imaging are generally classified according to certain parameters and used for detection of skin abnormalities and identification of the abnormalities whether they are pathological (e.g. tumors, melanoma, lesions) or benign (nevi). Changes in properties (like temperature of color) mark the boundaries between normal and abnormal (suspected cancerous) regions.
Recently, medium infrared MIR spectral methods have also been used to improve accuracy and reproducibility of biopsy evaluation for both gastric cancer [Naoko Fujioka, Yuji Morimoto, Tsunenori Arai, Makoto Kikuchi, “Discrimination between normal and malignant human gastric tissues by Fourier transform infrared spectroscopy”, Cancer Detection and Prevention 28, 32-36, (2004)] and lung cancer [Yang, Y., Josep Sule-Suso, Ganesh D. Sockalingum, Gregory Kegelaer, Michel Manfait, Alicia J El Haj, “Study of Tumor Cell Invasion by Fourier Transform Infrared Microspectroscopy”, Biopolymers, Vol. 78, 311-317 (2005); Wang, H. P., H. C. Wangb, and Y. J. Huang, “Microscopic FTIW studies of lung cancer cells in pleural fluid”, The Science of the Total Environment 204. 283-287, (1997)]. Samples, for spectral analysis, may be smaller than traditional biopsies. This makes the sampling procedure significantly less traumatic for the patient. Spectral analyzers may even be brought to a doctor's office or an operating room to allow real time diagnosis and treatment considerably increasing the efficiency of treatment as well as reducing expensive and dangerous time delays and reducing the chance of losing contact with patients.
Nevertheless, with the exceptions of visual inspection of reflected visible radiation (endoscopy) (for example see U.S. Pat. No. 6,975,898 B2 Seibel) and some limited research on auto fluorescence spectroscopy (for example see U.S. Pat. No. 5,876,995 Bryan and U.S. Pat. No. 7,172,553 Ueno et al.), optical analytical techniques have not been applied to in-vivo intra-orifice cancer detection and identification. Furthermore current art intra-orifice optical techniques use an active regime, applying radiation in the ultraviolet UV, visible or near-infrared NIR wave bands from an external source and measuring the reflection, absorption, refraction or fluorescence of the rays in the visible spectrum. There may be risks involved in exposing internal tissue to electromagnetic radiation even in the optical spectrum (because internal tissue is not naturally exposed to such radiation). Many of the widely known techniques of detection and identification of external pathologies have disadvantages making them not fully appropriate for detection and identification of internal cancers and cancer precursors. Furthermore new instruments have yet to be developed (and licensed) to permit application of these techniques to internal tissue in-vivo.
Although it has long been known that in-vivo heat differentials can be used to detect and identify cancer both in the lungs [Stefanadis, C., Christina Chrysohoou, Demosthenes B Panagiotakos, Elisabeth Passalidou, Vasiliki Katsi, Vlassios Polychronopoulos and Pavlos K Toutouzas, Temperature differences are associated with malignancy on lung lesions: a clinical study”, BMC Cancer, 3:1 doi:10.1186/1471-2407-3-1, (2003)] and in the gastrointestinal tract [Stefanadis C., Christina Chrysohoou, Emmanouel Paraskevas, Demosthenes B. Panagiotakos, Demetrios Xynopoulos, Dimitris Dimitroulopoulos, Kalliopi Petraki, Constantina Papadimitriou, Kyriakos Karoutsos, Christos Pitsavos and Pavlos K. Toutouzas, “Thermal Heterogeneity Constitutes A Marker for the Detection of Malignant Gastric Lesions In Vivo”, J Clin Gastroenterol 36(3):215-218, 2003], measurement of heat differentials of internal tissue has been limited to highly complex experimental studies using thermistors which must actually contact the area of measurement. Thermistor based temperature measurement may, in the future, be useful for identification of lesions, but measuring a temperature differential alone is not sufficient for positive identification of specific pathologies. Furthermore, for the purpose of detection, use of a thermistor is not at all feasible. Simply put, it is unthinkable that one would drag a thermistor across the entire inner surface of a subject's intestines to screen for pathologies. On the other hand, the use of heat cameras to sense temperature anomalies, as has been proposed for detecting skin cancer [for example using Forward Looking Infrared Sensors (FLIRS) and MIR pyroelectric cameras] with current art endoscopic techniques is not feasible because these cameras are heat sensitive and too large to be fit into an endoscope. Thus, current art techniques of endoscopic detection, which are based on imaging using a miniature camera located in the endoscope or a doctor using his eyes to detect a visible electromagnetic radiation signal through an optical fiber, are not applicable in the MIR spectrum.
There is thus a widely recognized need for, and it would be highly advantageous to have, a non-invasive methodology to detect and identify pathologic conditions of internal tissue in-vivo. The current invention fills this need.